The recommended daily dose of erlotinib was determined for patients with all types of non-small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR-tyrosine kinase inhibitor-naïve patients with sensitizing mutations were eligible. Clinical OD was determined in a phase I/II study based on the continual reassessment method (CRM) of both disease control and dose-limiting toxicity, defined as any toxicity of grade 2 (G2) or higher within 8 weeks. We also determined the pharmacologic OD via a pharmacokinetic (PK) study. Thirty-eight patients were enrolled. Clinical OD was 25 mg/day by the CRM. Median progression-free survival (mPFS) was 9.3 months. In receiver operating characteristic (ROC) analysis of mPFS, the trough concentration (C ) was ≥0.30 μg/ml. The area under the curve (AUC) and C were predicted via population PK (PPK) or a bootstrap of 100 iterations (PPK ). TOX20 was defined as <20% duration of any toxicity ≥G2 during the PFS period. In ROC analysis of mPFS and TOX20 in the PPK study, C was ≥0.17 and <0.32 μg/ml, respectively. In ROC analysis of mPFS and TOX20 in the PPK study, C was ≥0.15 and <0.31 μg/ml, AUC was ≥14.4 and <14.5 μg/ml•hr, and the dosage was ≥58.4 and <58.8 mg/day, respectively. Clinical and pharmacologic ODs were 25 by CRM and 50-60 mg/day by PK, respectively. The proposed starting OD is 50-60 mg/day, with personalized adjustment of 0.15-0.31 μg/mL based on C as determined by PPK monitoring.
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